11-β substituted-19-nor steroids

ABSTRACT

A compound selected from the group consisting of a compound of the formula   &lt;IMAGE&gt; I  wherein the substituents are defined as in the specification having anti-estrogen activity.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel 19-nor steriods offormula I and their non-toxic, pharmaceutically acceptable salts and aprocess and intermediates for their preparation.

It is another object of the invention to provide anti-estrogeniccompositions and a method of inducing anti-estrogenic activity inwarm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of a compound of the formula ##STR2## wherein R₁₇ and R'₁₇form ═O or R₁₇ is --OH or acyloxy of an organic carboxylic acid of up to12 carbon atoms and R'₁₇ is selected from the group consisting ofhydrogen and alkyl, alkenyl and alkynyl of up to 8 carbon atoms, alloptionally substituted with at least one member of the group consistingof halogen, --NH₂, optionally oxidized mono and di-alkylamino of 1 to 4alkyl carbon atoms, amino alkyl of 1 to 6 carbon atoms, dialkylaminoalkyl, dialkylamino-alkoxy, free or salified carboxy, carboxy esterifiedwith lower alkyl, alkyl of 1 to 8 carbon atoms optionally substitutedwith at least one halogen, acyl and acyloxy of an organic carboxylicacid of up to 6 carbon atoms, OH, ═O, --CN, --NO₂, formyl, alkoxy andalkylthio of 1 to 8 carbon atoms, carbamoyl, alkenyl and alkynyl of upto 8 carbon atoms, phenyl, furyl and thienyl, R₃ is selected from thegroup consisting of hydrogen, alkyl and cycloalkyl of up to 8 carbonatoms, acyl of an organic carboxylic acid of up to 12 carbon atoms andR₁ and R₂ are individually selected from hydrogen, alkyl and cycloalkylof up to 8 carbon atoms optionally substituted, an acyl radical of anorganic carboxylic acid of up to 12 carbon atoms and optionallysubstituted aryl and aralkyl of 1 to 6 alkyl carbon atoms and the arylis mono or polycyclic optionally containing at least one heteroatom ofsulfur, oxygen or nitrogen, R₂ is hydrogen and R₁ is selected from thegroup consisting of carbamoyl monosubstituted by alkyl or cycloalkyl ofup to 8 carbon atoms optionally substituted or aryl or aralkyl definedas above or R₁ and R₂ form a dialkylamino methylene of 1 to 4 alkylcarbon atoms or R₁ and R₂ together with the nitrogen to which they areattached form a saturated heterocycle of 5 to 6 ring members optionallycontaining a heteroatom of sulfur, nitrogen or oxygen optionallysubstituted with alkyl of 1 to 4 carbon atoms or ═O, n is an integer of1 to 18 and their non-toxic, pharmaceutically acceptable addition saltswith bases and acids.

Examples of acyloxy of an organic carboxylic acid of up to 12 carbonatoms are saturated or unsaturated aliphatic and cycloaliphaticcarboxylic acids such as an alkanoic acid like acetic acid, propionicacid, butyric acid or isobutyric acid, valeric acid or undecylic acid; ahydroxyalkanoic acid such as hydroxyacetic acid, a cycloalkylcarboxylicor cycloalkylalkanoic acid such as cyclopropyl carboxylic acid,cyclopentyl carboxylic acid or cyclohexylcarboxylic acid, cyclopentyl orcyclohexyl acetic acid or propionic acid, benzoic acid, salicylic acidor a phenylalkanoic acid such as phenyl acetic acid or phenyl propionicacid, an amino acid such as diethylamino acetic acid or aspartic acid,formic acid or an optionally salified di-carboxylic acid such asbutanedioic acid or the monosodium salt of the latter. It is preferablya derivative of acetic acid, propionic acid or butyric acid. By acyl ismeant the group corresponding to the preceding acyloxy groups.

Alkyl of 1 to 6 carbon atoms may be methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl,2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl,3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl,3,3-dimethylhexyl and 3-methyl-3-ethylpentyl and preferably methyl,ethyl, propyl or butyl.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, preferably cyclopentyl.

When R'₁₇ is alkenyl, it may be vinyl, propenyl, isopropenyl, allyl,2-methylallyl, butenyl or isobutenyl, preferably vinyl or propenyl WhenR'₁₇ is alkynyl it may be the ethynyl propynyl propargyl, butynyl orisobutynyl, preferably ethynyl or propynyl.

Examples of mono or polycyclic aryl or aralkyl are carbocyclicmonocyclic such as phenyl; a heterocyclic monocyclic such as thienyl,furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl,imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl, as wellas the position isomers of the heteroatom or heteroatoms which contain;a carbocyclic condensed ring, for example naphthyl or phenanthrenyl, aheterocyclic condensed ring, for example benzofuranyl, benzothienyl,benzimidazolyl, benzothiazolyl, naphtho [2,3-b]thienyl, thianthrenyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl,isoindolinyl, imidazopyridyl, imidazopyrimidinyl or the condensedpolycyclic systems constituted by heterocyclic monocyclics as definedabove such as furo[2,3-b]pyrrole or thieno[2,3-b]furan, and moreparticularly phenyl, furyl such as 2-furyl, imidazolyl such as2-imidazolyl, pyridyl such as 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidinyl such as pyrimid-2-yl, thiazolyl such as thiazol-2-yl,thiazolinyl such as thiazolin-2-yl, triazolyl such as triazol-2-yl,tetrazolyl such as tetrazol-2-yl, benzimidazolyl such asbenzimidazol-2-yl, benzothiazolyl such as benzothiazol-2-yl, purinylsuch as purin-7-yl or quinolyl such as 4-quinolyl, and an example of anaralkyl is methyl or ethyl substituted by one of the above aryls.

Examples of saturated nitrogenous heterocycle with 5 or 6 membersoptionally containing a second heteroatom chosen from nitrogen, oxygenand sulfur and optionally substituted by an alkyl or by carbonyl, ispreferably pyrrolidine, piperidine, piperazine, morpholine,thiamorpholine or imidazolidinone.

The optional substituents of the different groups above are preferablyselected from the group consisting of halogen such as fluorine,chlorine, bromine or iodine, amino, alkylamino such as methylamino orethylamino, dialkylamino such as dimethylamino, diethylamino,methylethylamino, each of these dialkylamino optionally being inoxidized form, aminoalkyl such as aminomethyl or aminoethyl,dialkylaminoalkyl such as dimethylamino methyl or ethyl,dialkylaminoalkyloxy such as dimethylamino ethyloxy, hydroxyl, freecarboxy esterified carboxy such as alkoxycarbonyl, such asmethoxycarbonyl or ethoxycarbonyl, or carboxy salified for example by asodium or potassium, alkyl of 1 to 8 carbon atoms such as methyl, ethylpropyl, isopropyl, butyl, isobutyl, tert-butyl optionally substituted byat least one halogen, for example fluorine such as trifluoromethyl, oxo,cyano, nitro, formyl, acyl such as acetyl, propionyl, butyryl, benzoyl,acyloxy such as acetoxy or --O--CO--(CH₂)_(n) CO₂ H in which n=1 to 5,alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,alkylthio such as methylthio, ethylthio, propylthio, isopropylthio,butylthio, carbamoyl, alkenyl such as vinyl, propenyl, alkynyl such asethynyl, propynyl and aryl such as phenyl, furyl, thienyl.

As an example of such substituted groups are alkyl substituted by one ormore halogen atoms, for example fluorine, such as trifluoromethyl,trifluorobutyl, pentafluoropropyl, pentafluorobutyl, pentafluoropentyl,heptafluorobutyl or nonafluorobutyl radical, or for example chlorinesuch as 2-chloroethyl. There can also be mentioned for example an arylsubstituted by one or more halogens, for example chlorine such as4-chlorophenyl.

Examples of suitable acids to form the acid addition salts when thecompounds of formula I have an amino group are inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid and organic acids such as acetic acid, formic acid,propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid,alkane sulfonic acids such as methane sulfuric acid or ethane sulfonicacid, arylsulfonic acids, such as benzene or p-toluene sulfonic acid andarylcarboxylic acids and when the compounds of formula I contain an acidfunction, examples of bases are salts of alkali or alkaline-earth metalsor of optionally substituted ammonium.

A preferred group of compounds are those of the formula ##STR3## whereinR₁ and R₂ are individually selected from the group consisting ofhydrogen, alkyl and cyclic alkyl of up to 8 carbon atoms optionallysubstituted, an acyl of an organic carboxylic acid of up to 12 carbonatoms, or optionally substituted phenyl, or R₁ is carbamoylmonosubstituted by an optionally substituted alkyl or cyclic alkyl of upto 8 carbon atoms, or by optionally substituted phenyl, and R₂ ishydrogen, or R₁ and R₂ form with the nitrogen atom to which they arelinked a cyclic urea of the formula ##STR4## n' being 2 or 3, or R₁ andR₂ form a dimethylaminomethylene and n is 1 to 7, as well as theaddition salts thereof.

Among the preferred compounds of formula I are those wherein R₁₇ is --OHand R'₁₇ is hydrogen, those wherein n is 5 or 6, those wherein R₁ and R₂are hydrogen or alkyl or cycloalkyl of up to 8 carbon atoms optionallysubstituted with at least one halogen, those wherein R₁ is hydrogen andR₂ is alkyl or cycloalkyl of up to 8 carbon atoms, those wherein R₂ ishydrogen and R₁ is carbamoyl monosubstituted with alkyl or cycloalkyl ofup to 8 carbon atoms or phenyl, all optionally substituted with at leastone halogen.

Specific preferred compounds of formula I areN-butyl-5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-pentanesulfonamide,N-butyl5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-N-methyl-pentanesulfonamideand 5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentanesulfonamide.

The process for the preparation for the compounds of formula I comprisesreacting a compound of the formula ##STR5## in which the phenol functionis optionally protected, A) either with a halogenated derivative of theformula

    X-(CH.sub.2).sub.n -SO.sub.2 -NR.sub.A R'.sub.A            III

in which X is halogen, n has the above meaning, R_(A) and R'_(A), areindividually selected from the group consisting of hydrogen, optionallysubstituted alkyl, acyl of an organic carboxylic acid, optionallysubstituted aryl or aralkyl with at least one of R_(A) and R'_(A) notbeing hydrogen or form with the nitrogen to which they are attached asaturated nitrogenous heterocycle with 5 or 6 ring members optionallycontaining a second heteroatom selected from nitrogen, oxygen and sulfurand optionally substituted by alkyl to obtain a compound of the formula##STR6## in which n R_(A) and R'_(A) have the same meaning subjectingthe latter to the action of an aromatization agent of ring A, andoptionally of an acylation agent of the 3-hydroxyl to obtain a productof the formula ##STR7## and in which n, R_(A) and R'_(A) have the abovemeaning and R₃ is hydrogen or an acyl, optionally subjecting the latterif necessary to one or more of the following reactions, in anyappropriate order:

reduction of the 17-ketone function

addition on the 17-ketone function of a metal complex of the formula

    M--R'.sub.17a                                              X

in which M is a metal and R'_(17a) has the same meaning as R'₁₇ with theexception of hydrogen,

selective acylation in position 17 when R₁₇ is hydroxyl,

alkylation or acylation of the 3-hydroxyl,

saponification when R₃ is acyl, optional salification by an acid or abase, B) or to the action of an aromatization agent of the A ring and toa protection reaction of the 3-hydroxyl, then to a selective eliminationreaction of the protective group of the 11-phenol to obtain a product ofthe formula ##STR8## in which Rp is a protective group, subjecting thelatter to the action of a compound of the formula

    X--(CH.sub.2).sub.n --SO.sub.2 --N═CH-N(Alk.sub.1) (Alk.sub.2)III'

X is halogen, Alk₁ and Alk₂ are alkyl of 1 to 4 carbon atoms and n is 1to 18, then to a hydrolysis reaction of the imine formed to obtain acompound of the formula ##STR9## in which n and Rp have the abovemeaning, being able if appropriate according to the nature of Rp, tocorrespond to a product of formula I, which product of formula VI isoptionally subjected and if necessary to one or more of followingreactions in any appropriate order:

elimination reaction of the Rp protective group

reduction of the 17-ketone function

addition on the 17-ketone function of a metal complex of the formula

    M--R'.sub.17a                                              X

as defined previously,

selective acylation in position 17 when R₁₇ is hydroxyl

alkylation or acylation of the 3-hydroxyl

action of a halide of the formula

    R.sub.B --X                                                VII

in which R_(B) is an optionally substituted alkyl or acyl and X ishalogen to obtain a compound of the formula ##STR10## in which n, R₁₇,R'₁₇ and R₃ have the above meanings

action of an isocyanate of the formula

    R.sub.c --NCO                                              VIII

in which R_(c) is alkyl, aryl or aralkyl, each being optionallysubstituted to obtain the compound of the formula ##STR11## in which n,R₁₇, R'₁₇ and R₃ have the above meanings

action of a compound of the formula

    (Alk.sub.3 O)(Alk.sub.4 O)CH--N(Alk.sub.1)(Alk.sub.2)      IX

in which Alk₁, Alk2, Alk₃ and Alk₄ are alkyl of 1 to 4 carbon atoms toobtain a compound of the formula ##STR12## in which n R₁₇, R'₁₇ and R₃have the above meanings

alkylation or acylation of the product of formula I_(B) by the action ofa halide of formula VII to obtain a corresponding dialkylated,diacylated or alkylacylated sulfonamide,

cyclization reaction of the product of formula I_(C) when R_(C) is--(CH₂)_(n) '--Hal n' being 2 or 3 and Hal is halogen to obtain theproduct of formula I'_(C) in which R₁ and R₂ form with the nitrogen towhich they are linked a cyclic urea of the type: ##STR13##

optional salification by an acid or a base.

The compounds of formula I_(A), corresponding to the compounds offormula I in which R₁ ═R_(A) and R₂ ═R'_(A), are obtained by reacting acompound of formula II successively with a) a compound of formula III inthe presence of a strong base such as sodium hydride in an aproticdipolar solvent such as dimethylformamide operating, for example, atambient temperature to obtain the intermediate compound of formula IV,b) an aromatization agent such as an acetyl bromide --acetic anhydridemixture followed by a saponification reaction carried out in thepresence of potassium hydroxide in methanol or sodium hydroxide inmethanol.

The compounds of formula VI are obtained by reacting a compound offormula II in which the 11-phenol is optionally protected successivelywith a) an aromatization agent such as palladium hydroxide on magnesiain methanol, followed by a protection reaction of the 3-hydroxy by theaction for example of benzyl chloride in the presence of potassiumcarbonate in acetone operating under reflux for 7 hours, and followed bya selective deprotection reaction of the 11-phenol, by a saponificationcarried out in the presence of potassium hydroxide in methanol or sodiumhydroxide in methanol to obtain the intermediate compound of formula V,b) a compound of formula III' in the presence of a strong base such assodium hydride in an aprotic dipolar solvent such as dimethylformamide,c) an acid hydrolysis agent of the imine formed in the preceding stagesuch as hydrochloric acid in a methanol--tetrahydrofuran mixture.

The compounds of formula I_(B) are obtained by reacting a compound offormula VI, in which OR_(p) is a hydroxyl protected by aralkyl with acompound of formula VII, the reaction being carried out in the presenceof sodium hydroxide in acetone under reflux or in the presence of sodiumhydride in dimethyl-formamide at ambient temperature. A secondalkylation or acylation can be carried out under the same operatingconditions.

The compounds of formula I_(C) are obtained by reacting a compound offormula VI, in which the protective group of the 3-hydroxyl iseliminated and the 17-ketone is reduced with a compound of formula VIIIoperating in the presence of a strong base such as sodium hydride in anaprotic dipolar solvent such as dimethylformamide operating, forexample, at ambient temperature. When R_(C) is of the (CH₂)_(n) '--Haltype, n' being 2 or 3, a cyclization reaction is produced in situ, themedium being very basic to form the compounds of formula I'_(C).

The compounds of formula I_(D) are obtained by reacting a compound offormula VI, in which the protective group of the 3-hydroxyl iseliminated and the 17-ketone is reduced, with a compound of formula IX,operating for example in dimethylformamide at ambient temperature.

When the compound of formula I contains a 17-ketone, the following areobtained:

the corresponding 17β-hydroxylated compound, for example by the actionof a reducing agent such as sodium borohydride in a neutral solvent suchas methanol,

the corresponding compound containing an R'₁₇ being alkyl alkenyl oralkynyl optionally substituted by the addition of a compound X such as alithium complex according to the process described in the EuropeanPatent EP No. 57,115.

It is well understood that if R'₁₇ is alkyl alkenyl or alkynyloptionally substituted by a reactive function, this may be provisionallyprotected by the usual methods.

When the compound of formula I possesses a 3-hydroxyl, the correspondingalkylated steroid is obtained by the action of an alkylation reagentsuch as alkyl iodide or alkyl sulfate for example methyl sulfate, or thecorresponding acylated steroid is obtained by the action of a standardacylation agent such as an acyl halide such as acetyl chloride.

When the compound of formula I possesses a 17β-hydroxyl, thecorresponding acyloxylated 17β steroid is obtained by the action of aselective acylation agent, for example acetic anhydride in pyridineoptionally in the presence of 4-dimethylamino-pyridine, or any other wayknown to a man skilled in the art.

The protective groups that can be used to protect the reactivefunctions, such as the hydroxyl function, are chosen from the usualgroups of organic chemistry and more particularly the chemistry of thepeptides. A non-exhaustive list of these groups as well as thecorresponding elimination methods will be found in French Patent No.2,499,995 whose content is incorporated by reference, as well as in thefollowing work: Protective group in organic synthesis (GREENE and WUTS(1991) Ed. WILEY).

The acetyl, benzoyl or terbutyldimethylsilyl can be mentioned forexample for the protection of the 11-phenol of the compound of formulaII. The acetyl, benzoyl or benzyl can be mentioned for example for theprotection of the 3-hydroxyl of the compounds of formulae V and VI.

For example, the protection reaction of the 3-hydroxyl with benzyl canbe carried out by the action of benzyl chloride in the presence of astrong base such as sodium hydride in a dipolar aprotic solvent such asdimethylformamide at ambient temperature, or by the action of benzylbromide in the presence of a weaker base such as potassium carbonate inacetone under reflux. This protection is useful because it is resistantto hydrolysis or saponification reactions.

When the intermediate compounds contain protected reactive functions,the corresponding deprotected compound is obtained by the action of theusual agents. A non-exhaustive list of these groups as well as thecorresponding elimination methods will be found in French Patent No.2,499,995 whose content is incorporated in by reference, as well as inthe following work: Protective group in organic synthesis (GREENE andWUTS (1991) Ed. WILEY).

Purely by way of indication, when the phenol is protected by acetyl, theelimination reaction of this protective group could be carried out usinga saponification agent such as potassium hydroxide in alcoholic medium.When the phenol is protected by a terbutyldimethylsilyl group, theelimination reaction of this protective group could be carried out usinga hydrolysis agent such as hydrochloric acid. When the 3-hydroxy isprotected by benzyl, the elimination reaction of this protective groupcould be carried out preferably by hydrogenolysis by the action ofhydrogen in the presence of a palladium catalyst on activated charcoalin an ethyl acetate/ethanol/acetic acid mixture.

In a preferred embodiment of the invention: the compounds of formula IIIare used in which X is preferably iodine, the compounds of formula III'are used in which X is preferably iodine, the compounds of formula VIIare used in which X is preferably iodine in the case where R_(B) isalkyl, and chlorine in the case where R_(B) is acyl.

The invention also extends to a process as defined above, characterizedin that at the start a compound is used corresponding to a compound offormula II containing in position 17, the R₁₇ and R'₁₇ substituents asdefined above

It goes without saying that in the implementation of such a process andas has already been mentioned for R'₁₇, intermediate protection of theR₁₇ and R'₁₇ may be necessary. This protection is as defined above. Theabove starting products are known, for example, from published EuropeanApplication No. 0,384,482, or are prepared by the processes described inthe Application, from 17-oxo steroids.

The novel anti-estrogenic compositions of the invention are comprised ofan anti-estrogenically effective amount of at least one compound offormula I and its non-toxic, pharmaceutically acceptable salts and aninert pharmaceutical carrier. The compositions may be in the form oftablets, dragees, capsules, granules, suppositories, pessaries,ointments, creams, gels, microspheres, implants, patches and injectablesolutions.

Examples of suitable excipients are talc, gum arabic, lactose, starch,magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents and preservatives.

The compositions of the invention also possess glucocorticoid orantiglucocorticoid, progestomimetic or antiprogestomimetic, androgen oranti-androgen, anti-mineralocorticoid, estrogen or anti-estrogenactivities. The compositions possess in particular a remarkableanti-estrogenis activity and anti-proliferative properties as is shownby the tests given further on.

These properties make the compositions useful for combating the sideeffects of glucocorticoids. They also allow the combating of disordersdue to a hypersecretion of glucocorticoids and notably ageing generallyand more particularly hypertension, delay in healing, atherosclerosis,osteoporosis, diabetes, obesity as well as immunosuppresion andinsomnia.

These compositions can also be used in the treatment of certain tumourswhich express the hormonal receptors for which the products of formula Ihave an affinity. The compositions which possess anti-progestomimeticproperties can be used to prepare original contraceptives, as agents forinterrupting pregnancy or as labour-inducing agents. These products canthus be used as period inducers for women and more generally forwarm-blooded female animals.

The products are therefore administered during periods when progesteroneplays an essential physiological role, that is to say during the lutealphase of the cycle, at the moment of nidation (or implantation of theembryo) and during pregnancy. A method of contraception of the inventionconsists of administering to the woman at least one of the products offormula I during 1 to 5 days preferably at the end of the cycle. Thisproduct is then preferably administered orally or in vagino but it canalso be used parenterally. The products can also be used by endonasalroute.

The products of formula I possessing anti-progestomimetic properties canalso be used against hormonal disturbances and, furthermore, they can beuseful in the treatment of hormone-dependent tumours. Their actions onthe hypophyseal secretions make the products usable in menopause.

These products can also be used in the synchronization of oestrus andthe synchronization of the dropping of young in farm animals,particularly bovines and ovines. The products can also be used tocontrol the fertility of domestic animals such as dogs or cats.

The compounds of formula I can also have progesto-mimetic properties andcan thus be used in the treatment of amenorrhea, dysmenorrhea and lutealinsufficiencies.

The compounds of formula I which possess anti-androgen properties can beused in the treatment of hypertrophy and cancer of the prostate,virilism, anaemia, hirsutism and acne as well as for male contraception.

The compounds of formula I which possess estrogen properties are alsousable in the treatment of disorders linked to a hypofolliculinemia, forexample amenorrhea, dysmenorrhea, repeated miscarriages, premenstrualdisorders, as well as in the treatment of the menopause andosteoporosis.

The anti-estrogen and anti-proliferative properties of the compounds offormula I make them useful in the treatment of hormone-dependentcarcinomas such as breast carcinomas and their metastases and in thetreatment of benign breast tumours.

The novel method of inducing anti-estrogenic activity in warm-bloodedanimals, including humans, comprises administering to warm-bloodedanimals an anti-estrogenically effective amount of at least one compoundof formula I and its non-toxic, pharmaceutically acceptable salts. Thecompound may be administered orally, rectally, parenterally ortopically. The usual effective daily dose is to mg/kg depending on thecondition treated, the compound and method of adminstration.

The compounds of formulae IV, V and VI are new intermediate products andamong the new intermediate products of the invention areN-butyl-5-[4-(Δ4,9-estradien-3,17-dione-11β-yl)-phenoxy]-N-methyl-pentanesulfonamide,5-[4-(Δ4,9-estradien-3,17-dione-11β-yl)-phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentanesulfonamide,11β-(4-hydroxyphenyl)-3-[benzyl-oxy]-Δ1,3,5(10)-estra-trien-17-one and5-[4-[17-oxo-3-[benzyl-oxy]-Δ1,3,5(10)-estra-trien-11β-yl]phenoxy]-pentanesulfonamide.

The compound of formula II necessary for the implementation of theprocess is described in European Patent Application No. 0,384,842(preparation of Example 43). Examples of the preparation of products offormulae III and III' appear in the experimental part. These compoundsare generally known, and are prepared by similar processes to thosedescribed in the experimental part.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

PREPARATION I N-[dimethylaminomethylene]-5-iodo-pentane-sulfonamide STEPA: 5-Chloropentane-sulfonamide

2.5 ml of a 28% aqueous solution of ammonium hydroxide were addeddropwise at 0° to +5° C. under an inert gas atmosphere to a solution of2.5 g of 5-chloropentane sulfonyl chloride (preparation described in:Bull. Soc. Chim. Belg. (1965) Vol. 74., p. 21) in 30 ml oftetrahydrofuran. The temperature was allowed to rise from 3° C. to 16°C., and the mixture was stirred at ambient temperature for 2 hours. Thetetrahydrofuran was evaporated under reduced pressure and the residuewas taken up in water, extracted with methylene chloride, washed withwater, then with an aqueous solution of sodium chloride, dried andevaporated under reduced pressure to obtain 2.01 g of the expectedproduct melting at 62° C.

    ______________________________________    IR Spectrum: Trichloromethane (CHCl.sub.3)    ______________________________________           --NH.sub.2                  3448 cm.sup.-1                  3352 cm.sup.-1           --SO.sub.2 --                  1344 cm.sup.-1                  1150 cm.sup.-1           --NH.sub.2                  1545 cm.sup.-1    ______________________________________

B: 5-chloro-N-[dimethylamino-methylene]-Pentane-sulfonamide STEP

1.29 ml of N,N-dimethylformamide-dimethyl acetal were added dropwise atambient temperature under an inert gas atmosphere to a solution of 1.5 gof the product of Step A in 8 ml of dimethylformamide. The solution wasstirred at ambient temperature for 3 hours, then poured into a 1%aqueous solution of sodium hydrogen sulfate, extracted with ethylacetate, washed with water, then with a saturated aqueous solution ofsodium chloride, dried and evaporated to dryness under reduced pressureto obtain 1.809 g of the expected product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --N═CH--N< 1629 cm.sup.-1    --SO.sub.2 --  1349 cm.sup.-1                   1119 cm.sup.-1    ______________________________________

STEP C: N-[dimethylamino-methylene]-5-iodo-pentane-sulfonamide

2.98 g of sodium iodide were added to a solution of 2.09 g of theproduct of Step B in 31.5 ml of methyl ethyl ketone (M.E.K.), and themixture was refluxed for 4 hours. After cooling, water was added andextraction was carried out with ethyl acetate. The extracts were washedwith water, then with a saturated aqueous solution of sodium chloride,dried and evaporated to dryness under reduced pressure to obtain 2.69 gof the expected product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --N═CH--N< 1629 cm.sup.-1    ______________________________________

PREPARATION 2 N-butyl-5-iodo-N-methyl-pentanesulfonamide STEP A:N-butyl-5-chloro-N-methyl-pentanesulfonamide

0.47 ml of N-butylmethylamine were added under an inert gas atmosphereto a solution of 410 mg of 5-chloropentane sulfonyl chloride in 10 ml ofmethylene chloride. The temperature rose from 13° C. to 26° C., and thenafter cooling to 0 to 5° C., 0.55 ml of triethylamine were added. Themixture was stirred at ambient temperature for 2 hours and the reactionmedium was poured into an aqueous solution of 1M hydrochloric acid,extracted with methylene chloride, washed with water, then with asaturated aqueous solution of sodium chloride, dried and evaporated todryness under reduced pressure to obtain 486 mg of the expected product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --SO.sub.2 --N<                 1334 cm.sup.-1, 1142 cm.sup.-1    ______________________________________

STEP B: N-butyl-5-iodo-N-methyl-pentanesulfonamide

526 mg of sodium iodide were added to a solution of 449 mg of theproduct of Step A in 4.5 ml of methyl ethyl ketone, and the mixture wasstirred at reflux for 4 hours. After cooling, the methyl ethyl ketonewas evaporated under reduced pressure and water was added. Extractionwas carried out with ethyl acetate and the extracts were washed withwater, then with a saturated aqueous solution of sodium chloride, driedand evaporated to dryness under reduced pressure to obtain 572 mg of theexpected product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --SO.sub.2 --N<                 1334 cm.sup.-1, 1141 cm.sup.-1    ______________________________________

PREPARATION 3N-(2,2,3,3,4,4,4-heptafluorobutyl)-5-iodo-N-methylpentanesulfonamideSTEP A:5-chloro-N-(2,2,3.3,4,4,4-heptafluorobutyl)-N-methylpentanesulfonamide

500 mg of N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylamine hydrochloride(obtained according to European Patent No. 384,842 Example 75) and then,at 0° to 5° C., 0.55 ml of triethylamine were added to a solution of 200mg of 5-chloropentane sulfonyl chloride in 5 ml of methylene chloride,and the mixture was stirred at ambient temperature for 2 hours. Waterwas added and extraction was carried out with methylene chloride. Theextracts were washed with water, then with a saturated aqueous solutionof sodium chloride, dried and evaporated to dryness under reducedpressure to obtain 378 mg of the expected product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --SO.sub.2 --N<                  1354 cm.sup.-1, 1341 cm.sup.-1, 1148 cm.sup.-1    Impurity C═O                  1730 cm.sup.-1    ______________________________________

STEP B:N-(2,2,3,3,4,4,4-heptafluorobutyl)-5-iodo-N-methylpentanesulfonamide

300 mg of sodium iodide were added to a solution of 355 mg of theproduct of Step A in 3 ml of methyl ethyl ketone and the mixture wasrefluxed for 4 hours. After evaporation of the solvent, the residue wastaken up in water and extracted with ethyl acetate. The extracts werewashed with an aqueous solution of sodium thiosulfate, then of sodiumchloride, and evaporated to dryness under reduced pressure to obtain 425mg of the expected product in the form of a colourless oil which slowlycrystallized.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    N--SO.sub.2 --               1354 cm.sup.-1, 1341 cm.sup.-1, 1148 cm.sup.-1    ______________________________________

PREPARATION OF EXAMPLE 111β-(4-hydroxyphenyl)-3-[(benzyl-oxy]-1,3,5(10)-estratrien-17-one STAGEA: 11β-[4-(benzoyloxy)-phenyl]-Δ4,9-estradiene-3,17-dione

3 ml of benzoyl chloride were added dropwise under an inert gasatmosphere at 0° to +5° C. to a solution of 8.758 g of11β-(4-hydroxyphenyl)-Δ4,9-estradiene-3,17-dione (prepared by Example 43of Patent EP No. 384,842) in 92 ml of acetone and 27 ml of 1M aqueoussodium hydroxide. At the end of the introduction of the benzoylchloride, precipitation of the benzoate was observed and the suspensionwas stirred for 10 minutes in an ice bath, then for 30 minutes atambient temperature. It was poured into an aqueous solution of 0.1Mhydrochloric acid and extracted with ethyl acetate. The extracts werewashed with a saturated aqueous solution of sodium chloride, dried andevaporated to dryness under reduced pressure to obtain 12.98 g of thecrude product which was crystallized from a methylene chloride/isopropylether mixture to obtain 9.93 g of the desired product melting at 196° C.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    >C═O in position 17 + ketone of                           1736 cm.sup.-1 (F)    Ar--O--CO--Ph:    conjugated ketone:     1659 cm.sup.-1                           1602 cm.sup.-1    Aromatic C═C's:    1505 cm.sup.-1                           1490 cm.sup.-1    ______________________________________

STEP B:11β-[4-(benzoyloxy)-phenyl]-3-hydroxy-Δ1,3,5(10)-estra-trien-17-one

10.1 g of palladium hydroxide at 20% on magnesium oxide were added to asolution of 10.07 g of the product of Step A in 104 ml of methanol andthe mixture was refluxed for 90 minutes. After cooling, the suspensionwas filtered and the insoluble catalyst was washed with a methylenechloride/methanol mixture 50/50. The filtrate was evaporated to drynessunder reduced pressure and the 10.72 g of residue were chromatographedon silica (eluant: ethyl acetate/cyclohexane 40/60) to obtain 7.72 g ofthe desired product melting at 265° C.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:               3599 cm.sup.-1    >C═O:           1733 cm.sup.-1 (F)                        1611 cm.sup.-1                        1602 cm.sup.-1    Aromatic C═C's: 1585 cm.sup.-1                        1508 cm.sup.-1    ______________________________________

STEP C:11β-[4-(benzoyloxy)-phenyl]-3-[benzyl-oxy]-Δ1,3,5(10)-estratrien-17-one

3.82 g of potassium carbonate and 4.9 ml of benzyl bromide (FlukaA007832) were added to a solution of 6,462 g of the product of Step B in110 ml of acetone and the mixture was refluxed for 7 hours. Then aftercooling, the mixture was evaporated to dryness under reduced pressureand the residue was taken up in ethyl acetate and poured into an aqueoussolution of 0.5M hydrochloric acid. Extraction was carried out withethyl acetate and the extracts were washed with a saturated aqueoussolution of sodium chloride, dried and evaporated to dryness underreduced pressure. The 12.2 g of residue were chromatographed on silica(eluant: ethyl acetate/cyclohexane 25/75) to obtain 6.68 g of thedesired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    >C═O:          1734 cm.sup.-1 complex                       1604-1608 cm.sup.-1                       1586 cm.sup.-1    Aromatic C═C's:                       1576 cm.sup.-1                       1508 cm.sup.-1                       1501 cm.sup.-1    ______________________________________

STEP D:11β-(4-hydroxyphenyl)-3-[benzyl-oxy]-Δ1,3,5(10)-estra-trien-17-one

12 ml of an aqueous solution of 2M sodium hydroxide were added to asolution of 6.64 g of the product of Step C in 87.5 ml of methanol and87.5 ml of tetrahydrofuran and the mixture was stirred for one hour atambient temperature. The reaction miture was poured into a 0.5M aqueoussolution of hydrochloric acid and extraction was carried out with ethylacetate. The extracts were washed with water, then with a saturatedaqueous solution of sodium bicarbonate, then with a saturated aqueoussolution of sodium chloride, dried and evaporated to dryness underreduced pressure to obtain 6.52 g of the expected crude product whichwas crystallized from methylene chloride to obtain 4.62 g of the desiredproduct melting at 240° C.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:                 3600 cm.sup.-1    >C═O:             1733 cm.sup.-1                          1613 cm.sup.-1                          1594 cm.sup.-1    Aromatic C═C:     1574 cm.sup.-1                          1513 cm.sup.-1                          1500 cm.sup.-1    ______________________________________

EXAMPLE 15-[4-(Δ,1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]pentanesulfonamide.STEP A:N-[dimethylamino-methylene]-5-[4-[3-benzyl-oxy]-Δ1,3,5(10)-estratrien-17-one-11β-yl]-phenoxy]-pentanesulfonamide

After stirring for 25 minutes, a solution of 2.67 g of the product ofPreparation 1 (Stage C) in 25 ml of dimethylformamide was added under aninert gas atmosphere to a suspension of 2.92 g of the product of Step Dof the preparation of Example 1 in 69 ml of dimethylformamide and 403 mgof sodium hydride at 50% in oil. The suspension was heated at 50° C. andafter 10 minutes, a solution was obtained which was stirred at thistemperature for 75 minutes. The solution was cooled to ambienttemperature and poured into a 1% aqueous solution of sodium hydrogensulfate and extracted with ethyl acetate. The extracts were washed withwater, then with a saturated solution of sodium thiosulfate and with asaturated aqueous solution of sodium chloride, dried and evaporated todryness under reduced pressure. The 6.75 g of residue werechromatographed on silica (eluant: ethyl acetate) to obtain 3.82 g ofthe desired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    >C═O in position 17:                       1733 cm.sup.-1    --N═CH--:      1629 cm.sup.-1                       1611 cm.sup.-1 (shoulder)                       1575 cm.sup.-1    Aromatic C═C's:                       1512 cm.sup.-1                       1500 cm.sup.-1    --SO.sub.2 --:     1349 cm.sup.-1    ______________________________________

STEP B:5-[4-[3-[benzyl-oxy]-Δ1,3,5(10)-estratrien-17-one-11β-yl]phenoxy]-pentanesulfonamide.

17.7 ml of 22° Be pure concentrated hydrochloric acid were added underan inert gas atmosphere, to a suspension of 3.818 g of the product ofStep A in 59 ml of methanol and 28 ml of tetrahydrofuran. The mixturewas heated to 80° C. for 90 minutes, and then, after cooling, it waspoured into a saturated aqueous solution of sodium bicarbonate.Extraction was carried out with ethyl acetate and the extracts werewashed with a saturated aqueous solution of sodium chloride, dried andevaporated to dryness under reduced pressure. The 4.15 g of residue waschromatographed on silica (eluant: ethyl acetate/cyclohexane 60/40) toobtain 2.89 g of desired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --NH.sub.2            3444 cm.sup.-1                          3350 cm.sup.-1    >C═O in position 17:                          1733 cm.sup.-1                          1610 cm.sup.-1    Aromatic C═C's:   1580 cm.sup.-1     +    --NH.sub.2 :          1545 cm.sup.-1    ______________________________________

STEPC:5-[4-[3-[benzyl-oxy]-Δ1,3,5(10)-estratrien-17β-ol-11β-yl]phenoxy]-pentanesulfonamide.

169 mg of and sodium borohydride were added at 0° to +5° C. under aninert gas atmosphere to a solution of 1.36 g of the product of Step B in6 ml of methanol and 6 ml of tetrahydrofuran. After stirring at 0° to+5° C. for one hour, the reaction mixture was poured into a 1M aqueoussolution of hydrochloric acid and extracted with ethyl acetate. Theextracts were washed with water, then with a saturated solution ofsodium chloride, dried and evaporated to dryness under reduced pressureto obtain 1,299 g of the expected crude product which were crystallizedfrom a methylene chloride/isopropyl ether mixture to obtain 1,295 g ofthe desired product melting at 146° C.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:             3609 cm.sup.-1    --NH.sub.2 :      3444 cm.sup.-1                      3353 cm.sup.-1                      1609 cm.sup.-1    Aromatic C═C's:                      1580 cm.sup.-1                      1512 cm.sup.-1, 1500 cm.sup.-1    --NH.sub.2 :      1544 cm.sup.-1    ______________________________________

STEP D: 5-[4-(Δ,1,3,5(10)-estratrien-3,17β-diol-11β-yl)-Phenoxy]pentanesulfonamide

161 mg of 10% palladium on activated charcoal (type E 10N, Degussa) wereadded to a solution of 1.295 g of the product of Step C in 50 ml ofethanol and 5 ml of acetic acid and then the mixture was stirred under ahydrogen pressure of 1640 mbar for 2 hours. After filtering, washing wascarried out with a methanol/methylene chloride mixture 1/1, followed byevaporating to dryness under reduced pressure. The acetic acid wasremoved by entraining with toluene to obtain 1.04 g of the expectedcrude product which was crystallized from ethanol to obtain 736 mg ofthe desired product melting at 175° C.

    ______________________________________    IR Spectrum: (Nujol)    ______________________________________    Complex absorption OH/NH region                          1616 cm.sup.-1    Aromatic C═C's:   1580 cm.sup.-1    + --NH.sub.2          1511 cm.sup.-    --SO.sub.2            1333 cm.sup.-1                          1153 cm.sup.-1    ______________________________________

EXAMPLE 2: N-butyl-5-[4-(Δ,1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-pentanesulfonamide STEPA: N-butyl-5-[4-[benzyl-oxy]-Δ1,3,5(10)-estratrien-17-one-11β-yl]-phenoxy]-pentanesulfonamide

0.188 ml of 1-iodobutane was added under an inert gas atmosphere to asolution of 500 mg of the product of Step B of Example 1 in 6.5 ml ofacetone and 0.96 ml of a 1M aqueous solution of sodium hydroxide and themixture was stirred at reflux for 52 hours. Then, the mixture was cooledbefore evaporating off the acetone under reduced pressure and theresidue was taken up in ethyl acetate and poured into a 0.5M aqueoussolution of hydrochloric acid and extracted with ethyl acetate. Theextracts were washed with water, then successively with a saturatedsolution of sodium thiosulfate and a saturated aqueous solution ofsodium chloride, dried and evaporated to dryness under reduced pressureto obtain 612 mg of product which was chromatographed on silica (eluant:ethyl acetate/cyclohexane 50/50) to obtain 68 mg of the desired productwith a Rf=0.40 ethyl acetate/cyclohexane 50/50.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --NH--:        approx. 3400 cm.sup.-1    >C═O:              1733 cm.sup.-1                           1610 cm.sup.-1    Aromatic C═C's:    1579 cm.sup.-1                           1511 cm.sup.-1                           1510 cm.sup.-1    --SO.sub.2 --          1327 cm.sup.-1 + 1141 cm.sup.-1    ______________________________________

STEP B:N-butyl-5-[4-[3-[benzyl-oxy]-Δ,1,3,5(10)-estratrien-17β-ol-11.beta.-yl]-phenoxy]-pentane-sulfonamide

33 mg of sodium borohydride were added under an inert gas atmospherecooled to 0° to +5° C. to a solution of 294 mg of the product of Step Ain 1.3 ml of tetrahydrofuran and 1.3 ml of methanol and the mixture wasstirred for one hour at 0° to +5° C. The mixture was poured into a 1Maqueous solution of hydrochloric acid and extracted with ethyl acetate.The extracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to dryness under reduced pressure toobtain 300 mg of product which was chromatographed on silica (eluant:ethyl acetate/cyclohexane 50/50) to obtain 194 mg of the desired productwith a Rf =0.25 ethyl acetate/cyclohexane 50/50.

STEP C:N-butyl-5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-pentanesulfonamide

44 mg of the 10% palladium catalyst on activated charcoal were added toa solution of 194 mg of the product of Step A in 5 ml of ethyl acetate,5 ml of ethanol and 5 ml of acetic acid and then the mixture was stirredunder a hydrogen pressure of 1700 mbar for 15 minutes. The suspensionwas filtered, washed with a 1/1 methanol/methylene chloride mixture. Thefiltrate was evaporated to dryness under reduced pressure and the aceticacid was entrained with toluene. Drying was carried out under reducedpressure to obtain 172 mg of the product which was chromatographed onsilica (eluant: methylene chloride/ isopropanol 96/4) to obtain 142 mgof the desired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:                 3601 cm.sup.-1    --NH--:               3400 cm.sup.-1                          1610 cm.sup.-1    Aromatic C═C's:   1581 cm.sup.-1                          1512 cm.sup.-1    --SO.sub.2 --         1327 cm.sup.-1                          1140 cm.sup.-1    ______________________________________

EXAMPLE 3:5-[4-(Δ1,3,5(10)-estratrien-3,17β-11β-yl)-phenoxy]-N[dimethylamino-methylene]-pentane-sulfonamide

0.062 ml of N,N-dimethylformamide-dimethylacetal were added to asolution of 200 mg of the product of Step D of Example 1 in 1.5 ml ofdimethylformamide, and the mixture was stirred for 90 minutes at ambienttemperature. The reaction mixture was poured into a 1% aqueous solutionof sodium hydrogen sulfate and extracted with ethyl acetate. Theextracts were washed with water, then with a saturated aqueous solutionof sodium chloride, dried and evaporated to dryness under reducedpressure to obtain 227 mg of product which was chromatographed on silica(eluant: methylene chloride/isopropanol 95/5) to obtain 168 mg of thedesired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:                 3602 cm.sup.-1    --N═CH--:         1629 cm.sup.-1                          1611 cm.sup.-1    Aromatic C═C's:   1580 cm.sup.-1                          1512 cm.sup.-1    ______________________________________

EXAMPLE4:N-butyl-N'-[5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11.beta.-yl)-phenoxy]-pentylsulfonyl]-urea

20 mg of sodium hydride were added under an inert gas atmosphere to asolution of 200 mg of the product of Step D of Example 1 in 2 ml ofdimethylformamide and, after 10 minutes of stirring at ambienttemperature, 0.046 ml of butyl isocyanate were added. After one hour ofstirring at ambient temperature, the reaction mixture was poured into a1M aqueous solution of hydrochloric acid and extracted with ethylacetate. The extracts were washed with a saturated aqueous solution ofsodium chloride, dried and evaporated to dryness under reduced pressureto obtain 317 mg of product which was chromatographed on silica (eluant:methylene chloride/isopropanol 95/5) to obtain 146 mg of the desiredproduct.

    ______________________________________    IR Spectrum: (nujol)    ______________________________________    OH/NH:        approx.   3360 cm.sup.-1                            + general absorption    >C═O:               1675 cm.sup.-1                            1610 cm.sup.-1    Aromatic C═C's:     1577 cm.sup.-1      + amide →      1540 cm.sup.-1                            1510 cm.sup.-1    --SO.sub.2 --:          1340 cm.sup.-1                            1146 cm.sup.-1    ______________________________________

EXAMPLE 5:N-(4-chlorophenyl)-N-[5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-pentylsulfonyl]-urea

22 mg of 50% sodium hydride were added under an inert gas atmosphere toa solution of 183 mg of the product of Step D of Example 1 in 2 ml ofdimethylformamide and, after 10 minutes of stirring at ambienttemperature, 73 mg of 4-chlorophenyl isocyanate were added. After 5hours of stirring at ambient temperature, the reaction mixture waspoured into a 1M aqueous solution of hydrochloric acid and extractedwith ethyl acetate. The extracts were washed with a saturated aqueoussolution of sodium chloride, dried and evaporated to dryness underreduced pressure to obtain 289 mg of product which was chromatographedon silica (eluant: methylene chloride/isopropanol 92.5/7.5) to obtain 86mg of the desired product.

    ______________________________________    IR Spectrum: (nujol)    ______________________________________    Complex absorption OH/NH:    >C═O:      approx.     1698 cm.sup.-1                               1607 cm.sup.-1    Aromatic C═C's:        1540 cm.sup.-1      + amide                  1511 cm.sup.-1                               1494 cm.sup.-1    ______________________________________

EXAMPLE 6:1-[5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-pentylsulfonyl]-2-imidazolidinone

20 mg of 50% sodium hydride were added under an inert gas atmosphere toa solution of 200 mg of the product of Step D of Example 1 in 2 ml ofdimethylformamide and, after 10 minutes of stirring at ambienttemperature, 0.035 ml of 2-chloroethylisocyanate were added. After 90minutes of stirring at ambient temperature, the reaction medium waspoured into a 1M aqueous solution of hydrochloric acid and extractedwith ethyl acetate. The extracts were washed with water, then with asaturated aqueous solution of sodium chloride, dried and evaporated todryness under reduced pressure to obtain 278 mg of product which waschromatographed on silica (eluant: ethyl acetate then methylenechloride/isopropanol 92.5/7.5) to obtain 102 mg of the desired product.

    ______________________________________    IR Spectrum: (nujol)    ______________________________________    General absorption OH/NH region:    >C═O:         1726 cm.sup.-1                      1612 cm.sup.-1    Aromatic C═C's:                      1580 cm.sup.-1                      1510 cm.sup.-1                      1505 cm.sup.-1 (shoulder)    --SO.sub.2 --:    1155 cm.sup.-1    ______________________________________

EXAMPLE7:N-butyl-5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-N-methyl-pentanesulfonamideSTEP A: N-butyl-5-[4-(Δ4,9-estradien-3,17-dione-11β-yl)-phenoxy]-N-methyl-pentanesulfonamide

362.5 mg of 11β-(4-hydroxyphenyl)-Δ4,9-estradiene-3,17-dione (Example 43of Patent EP No. 384,842) were added under an inert gas atmosphere to asuspension of 58 mg of sodium hydride at 50% in oil in 6 ml ofdimethylformamide and after stirring for 30 minutes at ambienttemperature, a solution of 417 mg of the product of Preparation 2 (StageB) in 1.5 ml of dimethylformamide was added. The temperature was allowedto rise from 23° C. to 27° C. during the introduction and then stirringwas carried out for 45 minutes. The reaction mixture was poured into a1M aqueous solution of hydrochloric acid and extracted with ethylacetate. The extracts were washed with water then successively with asaturated solution of sodium thiosulfate and a saturated aqueoussolution of sodium chloride, dried and evaporated to dryness underreduced pressure. The 883 mg of residue were chromatographed on silica(eluant: ethyl acetate/cyclohexane 60/40) to obtain 433 mg of thedesired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    >C═O in position 17:                       1735 cm.sup.-1    dienone            1658 cm.sup.-1                       1609 cm.sup.-1    C═C +          1600 cm.sup.-1 (shoulder)    Aromatic C═C's:                       1580 cm.sup.-1                       1509 cm.sup.-1 (strong)                       1333 cm.sup.-1    --SO.sub.2 N<:     1140 cm.sup.-1    ______________________________________

STEP B:N-butyl-5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-N-methyl-pentanesulfonamide

1) Aromatization

32 ml of acetic anhydride and 0.16 ml of acetyl bromide were added at 0°to +5° C. under an inert gas atmosphere to a solution of 404.5 mg of theproduct of Step A in 4 ml of methylene chloride and the mixture wasstirred for 15 minutes at this temperature, then 75 minutes at ambienttemperature.

2) Saponification of the acetate

0.3 ml of methanol were added to the reaction mixture cooled to 0° to+5° C., and after stirring for 10 minutes, evaporation to dryness wascarried out under reduced pressure at ambient temperature. The residuewas taken up in 2.4 ml of methanol and 2.4 ml of tetrahydrofuran and0.47 ml of sodium hydroxide were added. The mixture was stirred atambient temperature for 45 minutes.

3) Reduction of the 17-ketone

131 mg of sodium borohydride were added to the reaction mixture cooledto 0° to +5° C. and after stirring at ambient temperature for 45minutes, the reaction mixture was poured into a 1M aqueous solution ofhydrochloric acid. Extraction was carried out with ethyl acetate and theextracts were washed with water, then with a saturated solution ofsodium chloride, dried and evaporated to dryness under reduced pressure.The 393 mg of residue were chromatographed on silica (eluant: ethylacetate/cyclohexane 50/50) to obtain 193 mg of the desired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:                 3600 cm.sup.-1                          1610 cm.sup.-1    Aromatic C═C's:   1581 cm.sup.-1                          1512 cm.sup.-1    --SO.sub.2 N<:        1332 cm.sup.-1                          1138 cm.sup.-1    ______________________________________

EXAMPLE 8: 5-[4-(Δ1, 3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-pentanesulfonamideSTEP A:5-[4-(Δ4,9-estradiene-3,17-dione-11β-yl)-phenoxy]-N(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentane-sulfonamide

40 ml of sodium hydride at 50% in oil were added to a solution of 255 mgof 11β-(4-hydroxyphenyl)-Δ4,9-estradiene-3,17-dione (Example 43 ofPatent EP No. 384,842) in 4.5 ml of dimethylformamide and after stirringfor 30 minutes at ambient temperature, 400 mg of the product ofPreparation 3 (Step B) were added. The mixture was stirred at ambienttemperature for 45 minutes and the reaction mixture was poured into a 1Maqueous solution of hydrochloric acid and extracted with ethyl acetate.The extracts were washed successively with a saturated solution ofsodium thiosulfate and a saturated aqueous solution of sodium chloride,dried and evaporated to dryness under reduced pressure. The 600 mg ofresidue were chromatographed on silica (eluant: ethyl acetate/essence G55/45) to obtain 335 mg of the desired product.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    >C═O in position 17:                          1735 cm.sup.-1    dienone               1658 cm.sup.-1                          1609 cm.sup.-1    C═C +             1580 cm.sup.-1    Aromatic C═C's:   1509 cm.sup.-1                          1342 cm.sup.-1    --SO.sub.2 N<:        1148 cm.sup.-1    ______________________________________

STEP B:5-[4-(Δ1,3,5(10)-estratrien-3,17β-diol-11βyl)-Phenoxy]-N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentanesulfonamide

1) Aromatization

0.35 ml of acetic anhydride and 0.20 ml of acetyl bromide were added at0° to +5° C. to a solution of 430 mg of the product of Step A in 3.5 mlof methylene chloride, and the mixture was stirred for 40 minutes atambient temperature.

2) Saponification of the acetate

0.5 ml of methanol were added to the reaction mixture cooled to 0° to+5° C. and evaporation to dryness was carried out under reducedpressure. The residue was taken up in 3.5 ml of methanol and 0.6 ml ofsodium hydroxide were added.

3) Reduction of the 17-ketone

228 mg of sodium borohydride were added to the reaction mixture andafter stirring at ambient temperature for 20 minutes, acidification wascarried out to pH=2 with 2N hydrochloric acid, followed by extractionwith methylene chloride. The extracts were dried and evaporated todryness under reduced pressure. The 429 mg of residue werechromatographed on silica (eluant: ethyl acetate/essence G 40/60) toobtain 266 mg of the desired product melting at 136° C.-138° C.

    ______________________________________    IR Spectrum: (CHCl.sub.3)    ______________________________________    --OH:                 3615 cm.sup.-1                          1610 cm.sup.-1    Aromatic C═C's:   1581 cm.sup.-1                          1512 cm.sup.-1                          1491 cm.sup.-1    --SO.sub.2 N<:        1342 cm.sup.-1                          1148 cm.sup.-1    ______________________________________

Pharmaceutical compositions

Tablets were prepared containing 50 mg of the product of Example 7 andsufficient excipient of talc, starch, magnesium stearate for a tablet of120 mg.

Injectable suspensions were prepared containing 25 mg of the product ofExample 7 and sufficient excipient of dispersive aqueous solution:benzyl alcohol, polysorbate 80, carboxymethylcellulose (sodium salt),sodium chloride, water for injectable preparations of 1 ml.

Pharmacological study

1--Activity on the hormonal receptors using either the natural hormonalreceptor of a rat (AR), or the recombinant human receptor (PR, GR andER).

Androgen receptor of the prostate of a rat

Male Sprague Dawley EOPS rats weighing 180 to 200 g were castrated and24 hours after the castration, the animals were sacrificed. Theprostates were removed, weighed and homogenized at 0° C. using a Potterteflon-glass in a TS buffered solution (10 mM Tris, 0.25 M saccharose, 2mMDTT, 20 mM MoNa, 0.1 mM PMSF, pH 7.4) (1 g of tissue per 8 ml of TS).The homogenate was centrifuged (209,000 g for 30 minutes) at 0° C.Aliquots of the supernatant were incubated at 0° C. for 24 hours with aconstant concentration (T) of tritiated testosterone in the presence ofincreasing concentrations, either of unlabelled testosterone (0 to1000×10⁻⁹ M), or of the product under test (1 to 25000×10⁻⁹ M). Theconcentration of bound tritiated testosterone (B) was measured in eachincubate by the technique of adsorption with carbon dextran.

Human progesterone receptor

The recombinant human progesterone receptor was obtained bysuperexpression in an insect-Baculovirus cell system by methodologydescribed by WEBB et al. in Journal of Methods in Cell and MolecularBiology, (1990), Vol. 2 N° 4, pp. 173-188 and whose use is described forthe expression of human hormonal receptors, for example the humanglucocorticoid receptor (SRINIVASAN et al. Molecular Endocrinology,(1990), Vol. 4 N° 2, pp. 209-216).

The BaculoGold Transfection Kit was used (PharMingen, reference 21000K)to insert the cDNA fragment described by KASTNER et al. (The EMBOJournal, (1990), Vol. 9 N° 5, pp. 1603-1614), containing the regioncoding for the human progesterone receptor and to prepare thecorresponding recombinant virus. The recombinant virus was used toexpress the progesterone receptor in SF9 insect cells (ATCC CRL1711), bythe known methodology mentioned previously.

2×10⁷ to 2.5×10⁷ SF9 cells were cultivated in a 172 ml "Falcon" flask ina TNM-FH "SIGMA" medium supplemented with 10% of foetal calf serum (FCS)and with 50 micrograms/ml of gentamycin. After infection, thenincubation at 27° C. for 40 to 42 hours, the cells were lysed in 1 ml oflysis buffer (1) by a freezing-defrosting cycle which was repeated twicemore. The supernatant containing the recombinant human progesteronereceptor was kept in liquid nitrogen in doses of 1 ml. The supernatantwas diluted at the time of use according to a dilution range varyingfrom 1/10th to 1/100th with 10 mM Tris, 0.25 M saccharose, HCl buffer atpH 7.4 containing 0.1% gelatin and then was incubated at 0° C. for 24hours with a constant concentration (T) of tritiated17α,21-dimethyl-19-nor-Δ4,9-pregnadien-3,20-dione in the presence ofincreasing concentrations either of unlabelled progesterone (0-2500×10⁻⁹M), or of unlabelled product under test (1 to 25000×10⁻⁹ M). Theconcentration of bound tritiated 17,21-dimethyl19-nor-Δ4,9-pregnane-3,20-dione (B) was then measured in each incubateby the technique of adsorption with carbon dextran.

Human glucocorticoid receptor

A supernatant of SF9 cells containing the recombinant humanglucocorticoid receptor was obtained by the process described above forthe progesterone receptor using the cDNA fragment described HOLLENBERGet al. (Nature (1985), Vol. 318 No. 19/26, p. 635) containing the regioncoding for the human glucocorticoid receptor. The cells were lysed in alysis buffer (2). The supernatant was incubated at 0° C. for 24 hourswith a constant concentration (T) of6,21-dimethyl-Δ1,4,6-pregnatrien-11β,17β-diol-20-yn-3-one tritiated inthe presence of increasing concentrations either of unlabelleddexamethasone (0-1000×10⁻⁹ M), or of the unlabelled product under test(1 to 25000×10⁻⁹ M). The concentration of bound tritiated6,21-dimethyl-Δ1,4,6-pregnatrien-11β,17β-diol-20-yn-3-one (B) was thenmeasured in each incubate by the technique of adsorption with carbondextran.

Human estrogen receptor

A supernatant of SF9 cells containing the recombinant human estrogenreceptor was obtained by the process described above for theprogesterone receptor using the cDNA fragment described in the HEGOexpression vector by TORA et al. (EMBO Journal (1989), Vol. 8 N° 7, pp.1981-1986), containing the region coding for the human estrogen receptorof "wild type" with a glycine in position 400. The cells were lysed inthe lysis buffer (1). The supernatant was incubated at 0° C. for 24hours with a constant concentration (T) of tritiated estradiol in thepresence of increasing concentrations either of unlabelled estradiol(0-1000×10⁻⁹ M), or of the unlabelled product under test (1 to25000×10⁻⁹ M). The concentration of bound tritiated estradiol (B) wasthen measured in each incubate by the technique of adsorption withcarbon dextran.

Expression of the results and methods of calculation

Calculation of the relative bond affinity (RBA).

The following 2 curves were traced: percentage of bound tritiatedhormone B/BO as a function of the logarithm of the concentration ofunlabelled reference hormone or as a function of the logarithm of theconcentration of the unlabelled product under test.

The straight line of the following equation was determined:

    I.sub.50 =100 (BO/BO+Bmin/BO)/2 i.e. I.sub.50 =100 (1+Bmin/BO)/2=50 (1+Bmin/BO)

BO=Concentration of bound tritiated hormone in the absence of anyunlabelled product,

B=Concentration of bound tritiated hormone in the presence of aconcentration X of unlabelled product,

B min=Concentration of bound tritiated hormone in the presence of alarge excess of cold reference hormone (500 nM). The intersections ofthe straight line I₅₀ and the curves allowed the evaluation of theconcentrations of unlabelled reference hormone (CH) and of theunlabelled product under test (CX) which inhibited by 50% the specificbinding of the tritiated hormone on the receptor.

The relative bond affinity (RBA) of the product under test wasdetermined by the equation:

    RBA=100 (CH/(CX)

The RBA's of the reference products estradiol, progesterone,dexamethasone and testosterone were arbitrarily taken to be equal to100. The results of the RBA's obtained were the following:

    ______________________________________                    hGR    Products           hER      Dexa-      hPR      AR    of     Estradiol                    methasone  Progesterone                                        Testosterone    Example           = 100    = 100      = 100    = 100    ______________________________________    2      21       82         37       3    7      4        152        111      2.5    8      19       114        55       1.5    ______________________________________

Conclusion

The products studied, particularly the products of Examples 2 and 8,have a marked affinity for the estrogen receptor. The products ofExamples 2, 7 and 8 have a marked affinity for the glucocorticoid andprogesterone receptors.

Lysis buffers: (1) Tris-HCl pH 8: 20 mM, EDTA: 0.5 mM, DTT: 2 mM,glycerol: 20%, KCl: 400 mM, PIC 1°/oo.

(2) Potassium phosphate pH 7.0: 50 mM, DTT: 5 mM, glycerol: 20%, Sodiummolybdate: 20 mM, PIC 1°/oo.

PIC: leupeptin, pepstatin A, aprotinin, antipaine, chymostatin.

Final concentration of each one: 2.5 ug/ml

2--Anti-proliferative activity on the growth of MCF-7 human breasttumour cells

Description of the test

a) Cell culture

The MCF-7 lines were maintained in culture in a base medium (accordingto 1) containing 5% of foetal calf serum at 37° C. under a humidatmosphere containing 5% CO₂. The subconfluent cells were collected bytrypsination (0.1% trypsin, 0.02% EDTA) and then rinsed by gentlecentrifuging. A sample of the cells in suspension was counted with aMalassez cell.

b) Study of the growth

The cells were resuspended in a base medium without phenol red in thepresence of 5% of steroid-free FCS, and stimulated either by 0.1 nM ofestradiol, or by 10 ng/ml of EGF+1 ng/ml of PDGF. The cells were seededat a rate of 50,000 cells per well in multi-well plates (24 wells of 2.5cm²). Twenty-four hours after the seeding (DO), the product to be testedwas added to the mixture in ethanolic solution (final concentration ofethanol: 0.1%), at a concentration of 10⁻¹¹ to 10⁻⁶ M, the control wellsreceiving the same concentration of ethanol. The media containing theproducts were renewed every 48 hours. At the end of the experiment (D7to D9), the mixture was extracted and the cells were immediately fixedwith 250 microliters of methanol to dose the DNA. The anti-proliferativeactivity of the products was evaluated by their capacity to inhibit theincrease of DNA relative to the control.

c) DNA dosage

The DNA was dosed by a fluorimetric method using DABA (3,5diaminobenzoicacid) (according to 2): 200 microliters of DABA were added to each welland the plates were incubated for 45 minutes at 56° C. Then, 2 ml of 1NHCl were added and the fluorescence was measured using a fluorimeter(excitation wavelength: 408 nm, emission wavelength: 510 nm). Thequantity of DNA per well was evaluated relative to a reference scaleobtained by treating a calf thymus DNA standard under the sameconditions.

Results

The concentration in nM which inhibited by 50% the growth of the MCF-7cells stimulated by EGF +PDGF (IC₅₀) was determined in the mannerindicated above.

Results

Product of Example 2:IC₅₀ =0.016 nM

Product of Example 7:IC₅₀ =0.015 nM

Product of Example 8:IC₅₀ =0.026 nM

(1) A base medium was prepared as follows:

MEM medium (Minimal Essential Medium) to which were added:

1% non-essential amino acids (GIBCO),

peni-strepto (100 U/ml penicillin, 0.1 mg/ml streptomycin),

0.1% fungizone,

2 mM glutamine,

2.25 mg/ml sodium bicarbonate.

(2) Puzas and Goodman, Analytical Biochemistry, Vol. 86, p. 50, 1978.

Various modifications of the compounds and method of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound of the formula ##STR14## wherein R₁₇ andR'₁₇ form ═O or R₁₇ is --OH or acyloxy or an organic carboxylic acid ofup to 12 carbon atoms andR'₁₇ is selected from the group consisting ofhydrogen, alkyl, alkenyl and alkynyl, said alkyl, alkenyl and alkynyleach having up to 8 carbon atoms and wherein said alkyl, alkenyl andalkynyI groups are optionally substituted by at least one memberselected from the group consisting of halogen, --NH₂, alkylamino of 1 to4 carbon atoms, dialkylamino of 1 to 4 alkyl carbon atoms, amino alkylof 1 to 6 carbon atoms, dialkylaminoalkyl, dialkylaminoalkoxy, freecarboxy, salified carboxy, carboxy esterified with lower alkyl, alkyl of1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms substituted with oneor more halogens atoms, acyl of an organic carboxylic acid of up to 6carbon atoms, acyloxy of an organic carboxylic acid of up to 6 carbonatoms, OH, ═O, --CN, --NO₂, formyl, alkoxy of 1 to 8 carbon atoms,alkylthio of 1 to 8 carbon atoms, carbamoyl, alkenyl of up to 8 carbonatoms, alkyl of up to 8 carbon atoms and phenyl, R₃ is selected from thegroup consisting of hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkylof up to 8 carbon atoms and acyl of an organic carboxylic acid of up to12 carbon atoms and R₁ and R₂ are each individually selected from thegroup consisting of hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkylof up to 8 carbon atoms, alkyl of 1 to 8 carbon atoms substituted withone or more halogen atoms, cycloalkyl of up to 8 carbon atomssubstituted with one or more halogen atoms, acyl of an organiccarboxylic acid of up to 12 carbon atoms, monocarbocyclic aryl andmonocarbocyciic aralkyl having 1 to 6 alkyl carbon atoms, wherein saidalkyl, cycloalkyl, halogen substituted alkyl, halogen substitutedcycloalkyl, monocarbocyclic aryl and monocarbocyclic aralkyl are eachoptionally substituted with a member selected from the group consistingof halogen, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, dialkylaminoalkloxy, hydroxyl, free carboxy, carboxyesterified with alkyl of 1 to 4 carbon atoms, salified carboxy, alkyl of1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms substituted by one ormore halogens, oxo, cyano, nitro, formyl, acyl of an organic carboxylicacid of up to 12 carbon atoms, alkoxy, alkylthio, alkenyl of up to 3carbon atoms, alkynyl of up to 3 carbon atoms, phenyl and phenylsubstituted by one or more halogen atoms, or R₂ is hydrogen and R₁ isselected from the group consisting of carbamoyl monosubstituted by amember selected from the group consisting of alkyl of 1 to 8 carbonatoms, alkyl of 1 to 8 carbon atoms substituted by one or more halogenatoms, cycloalkyl of up to 8 carbon atoms substituted by one or morehalogen atoms, monocarbocyclic aryl and monocarbocyclic aralkyl whereinsaid monocarbocyclic aryl and monocarbocylic aralkyl are each optionallysubstituted by one or more halogen atoms or a member selected from thegroup consisting of --NH₂, alkylamino of 1 to 4 carbon atoms,dialkylamino of 1 to 4 carbon atoms, aminoalkyl of 1 to 2 carbon atoms,dialkylamino alkyl of up to 6 carbon atoms, dialkylaminoalkoxy, freecarboxy, salified carboxy, carboxy esterified with lower alkyl, alkyl of1 to 8 carbon atoms, alkyl of 1 to 8 carbon atoms substituted with oneor more halogens, acyl of a monocarbocyclic acid of up to 6 carbonatoms, acyloxy of an organic carboxylic acid of up to 6 carbon atoms,OH, ═O, --CN, --NO₂, formyl, alkoxy of 1 to 8 carbon atoms, alkylthio of1 to 8 carbon atoms, carbamoyl, alkenyl of up to 8 carbon atoms, alkylof up to 8 carbon atoms and phenyl and phenyl substituted with one ormore halogen atoms, n is an integer of 1 to 18 or its non-toxic,pharmaceutically acceptable addition salt with a base or acid.
 2. Acompound of claim 1 having the formula ##STR15## wherein R₁ and R₂ areeach individually selected from the group consisting of hydrogen, alkylof 1 to 8 carbon atoms and cycloalkyl wherein both alkyl and cycloalkylare optionally halo substituted, acyl of an organic carboxylic acid of 1to 12 carbon atoms and phenyl which is optionally halo substituted orR₂is hydrogen and R₁ is a member selected from the group consisting ofcarbamoyl optionally substituted with alkyl of 1 to 8 carbon atoms,cycloalkyl of up to 8 carbon atoms optionally halo substituted, acyl ofan organic carboxylic acid of up to 12 carbon atoms, phenyl and halosubstituted phenyl.
 3. A compound of claim 1 wherein R₁₇ is --OH andR'₁₇ is hydrogen.
 4. A compound of claim 1 wherein n is 5 or
 6. 5. Acompound of claim 1 wherein R₁ and R₂ are hydrogen.
 6. A compound ofclaim 1 wherein R₁ is hydrogen and R₂ is alkyl of 1 to 8 carbon atoms orcycloalkyl of up to 8 carbon atoms.
 7. A compound of claim 1 wherein R₁and R₂ are each alkyl of 1 to 8 carbon atoms or cycloalkyl of up to 8carbon atoms each optionally substituted with at least one halogen.
 8. Acompound of claim 1 wherein R₂ is hydrogen and R₁ is carbamoylmonosubstituted with alkyl of 1 to 8 carbon atoms cycloalkyl of up to 8carbon atoms or phenyl, all optionally substituted with at least onehalogen.
 9. A compound of claim 1 selected from the group consistingofN-butyl-5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-pentanesulfonamide,N-butyl-5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-N-methyl-pentanesulfonamide,5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-N(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentanesulfonamide.
 10. An anti-estrogenic compositioncomprising an anti-estrogenically effective amount of a compound ofclaim 1 and an inert, pharmaceutical carrier.
 11. A composition of claim10 wherein the active compound is selected from the group consistingofN-butyl-5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)phenoxy]-pentanesulfonamide,N-butyl-5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-N-methyl-pentanesulfonamide,5-[4(Δ1,3,5(10)-estratrien-3,17β-diol-11β-yl)-phenoxy]-N(2,2,3,3,4,4,4-heptafluorobutyl)-N-methyl-pentanesulfonamide.